A-nor-d-homosteroids



United States Patent Oflice 3,385,883 Patented May 28, 1968 3,385,883 A-NOR-D-HOMOSTEROIDS Seymour D. Levine, North Brunswick, N.J., assignor to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Mar. 17, 1966, Ser. No. 534,996 4 Claims. (Cl. 260-488) This invention relates to and has as its object the provision of new physiologically active steroids, processes for their production and novel inter-mediates useful in the preparation thereof.

More particularly, this invention relates to A-nor-D- homo-17-methyl steroids having the formula I CH3 where-in R is selected from the group consisting of hydrogen and acyl.

The preferred acyl and acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acid (e.g., acetic, propionic, butyric and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and fi-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The novel compounds of this invention are pharmacologically active substances which possess anti-androgenie activity (i.e., they inhibit the actions of androgens), and which may be used in the treatment of such conditions as hyperandrogenic acne.

The compounds may be formulated for such administration, the concentration and/ or dosage being based on the activity of the particular compound and the requirements of the patient.

The compounds of this invention may be prepared according to the processes of this invention beginning with 17a-hydroxy-A-norprogesterone. This starting material may be prepared by the process disclosed in copending U.S. patent application, Ser. No. 399,838, filed Sept. 28, 1964.

The starting material may be treated with boron fluoride etherate in the presence of an acid anhydride to yield the 17fi-methyl-A -A-nor-D-homoandrostane-2,17adione-17a-o1 acyl compounds of this invention. Deacylation of this compound may be accomplished by treating it with a potassium carbonate in alcohol (e.g., methanol) solution. From this reaction I7B-methyl-A -A-nor-D- homoandrostene-2,17a-dione-17a-ol is recovered. This latter compound may be treated with thionyl chloride to yield the A -compound of this invention.

The following examples illustrate this invention; all temperatures are in degrees centigrade unless otherwise specified.

Example 1.l7B-methyl-A -A-nor-D-homoandrostene- 2, l7a-dione-l7u-ol acetate A solution of 824 mg. of 17ot-hydroxy-A-norprogesterone in 80 mml. of glacial acetic acid is treated with 3.2 ml. of acetic anhydride and 3.2 ml. of boron fluoride etherate and left at room temperature for sixteen hours. The reaction mixture is treated with ml. water and concentrated to a small volume, diluted with water and extracted with ether. The ether extracts are washed with sodium bicarbonate solution, 8% salt solution, dried (sodium sulfate) and evaporated to dryness. The residue is crystallized from ether-hexane to give 505 mg. of crystalline material which is plate chromatographed on neutral alumina (Activity V) as the adsorbent and developed with chloroform. Elution of the major ultraviolet absorbing band with ethyl acetate gives a residue which is crystallized from chloroform-isopropyl ether to afford 285 mg. of l7B-methyl-A -A-nor-D- homoandrostene-2,17a-dione-l7a-ol acetate, M.P. 151. The analytical sample is prepared by recrystallization from chloroform-isopro'pyl ether, M.P. ISO-151,

a 5.80 (at 5.87, 5.96. and 6.17,u; i539 233 my (15,200 5 5%, 8.92 (8., 18-Me), 8.84 (s., 19-Me) 8.54 (8., 17B-Me), 7.99 (s, Not-acetate) and 428 (8., 3-1-1).

Analysis.Calcd for c u o, (358.46): c, 73.71; H, 8.44. Found: c, 73.85; H, 8.45.

Example 2.l7,B-methyl-A -A-nor-D-homoandrostene- 2,17a-dione-l7a-ol A mixture of mg. of l7p-methyl-A -A-nor-D- homoandrostene-Z,l7a-dione-l7a-ol acetate and 1.5 ml. of 10% potassium carbonate solution in 15 ml. of methanol is left at room temperature for seventeen hours. The reaction mixture is diluted with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried (sodium sulfate) and evaporated to dryness to give 117 mg. of 17B-methyl-A -A- nor D homoandrostene-2,l7a-dione-l7a-ol, M.P. 163- 164. The analytical sample is prepared by recrystallization from chloroformisopropyl ether, M.P. 170.5 171.5; X 2.85, 5.95 and 6.l5y.;

r5 22? 233 m (16,800); 18%,, 8.82 (5., 18Me), 8.82 (5., l9-hgle), 8.58 (5., 17B-Me), 6.03 (17a-OH) and/1.28

Analysis.-Calcd for C H O (316.42): C, 75.9l; H. 8.92. Found: C, 76.23; H, 9.01.

Example 3.-17-methyl-A -A-nor-D-homoandrosta. diene-2,17a-dione A solution of 30 mg. of 17fl-methyl-A -Anor-D-homoandrostane-Z,l7a-dione-l7a-ol in 3 ml. of pyridine at 20 is treated with a solution of 0.04 ml. of thionyl chloride in 0.4 ml. of pyridine. After 0.5 hours at icebath temperature, the reaction mixture is diluted with water and extracted with chloroform. The chloroform extracts are Washed with 2 N hydrochloric acid, 8% salt solution, dried (sodium sulfate) and evaporated to dryness. Plate chromatography of the residue using neutral alumina (Activity V) as the adsorbent and chloroform as the developing solvent gives a major ultraviolet absorbing band. Elution with ethyl acetate gives a residue which is crystallized from chloroform-isopropyl ether to give 6 mg. of 17-methyl-A -A-nor-D-homoandrostadiene- 2,17a-dione, M.P. l76-l77, x234 m (25,800).

Analysis.Calcd for C H O (298,41): C, 80.49; H, 8.78. Found: C, 80.20; H, 9.18.

The invention may be variously otherwise embodied Within the scope of the appended claims.

wherein R is selected from the group consisting of hydrogen and acyl derived from hydrocarbon carboxylic acids having less than twelve carbon atoms.

1 2. A compound in accordance with claim 1 having the name 17/? methyl A A-nor-D-homoandrostene-Z, l7adione-17a-ol acetate.

3. A compound in accordance with claim 1 having the name 175 methyl A A-nor-D-homoandrostene-Z,17adione-17a-o1.

4. A compound having the name l7-methy1-A -A- nor-D-homoandrostadiene-2,17a-dione.

References Cited UNITED STATES PATENTS o VIVIAN GARNER, Assisimnt Examiner. 

1. A STEROID HAVING THE FORMULA 